Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death

Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross‐resistance to a wide range of DNA‐damaging drugs

“…(25,26) For detection of ROS accumulation, cells treated with various agents were incubated for 30 min at 37°C with 10 µM 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H 2 DCFDA; Molecular Probes), harvested by exposure to trypsin, and then monitored for fluorescence with a FACSCalibur flow cytometer as described. (14) Immunoblot analysis. Cell lysates were fractionated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and subjected to immunoblot analysis as described.…”

“…Several small-molecule HDAC inhibitors have recently been shown to exhibit potent and specific anticancer activity in preclinical studies. (10)(11)(12)(13)(14) Multiple mechanisms have been proposed for the anticancer activity of HDAC inhibitors, which include the enhanced acetylation of core histones and consequent increased accessibility of genomic DNA to transcriptional complexes, resulting in the induction of tumor suppressor genes.(10,15) The hyper-acetylation of histones induced by the HDAC inhibitor trichostatin A (TSA) has been shown to increase chromatin accessibility by measurement of the size-dependent nuclear distribution of microinjected fluorescein isothiocyanate-dextran conjugates with the use of image-correlation spectroscopy.(16) Such an HDAC inhibitorinduced relaxation of chromatin structure would be expected to increase chromatin accessibility not only to transcription factors but also to therapeutic agents that target genomic DNA. Consistent with this notion, HDAC inhibitors have been shown to sensitize tumor cells to the induction of cell death by ionizing radiation, (17,18) ultraviolet (UV) radiation, (19) and several DNA-damaging drugs.…”

“…Several small-molecule HDAC inhibitors have recently been shown to exhibit potent and specific anticancer activity in preclinical studies. (10)(11)(12)(13)(14) Multiple mechanisms have been proposed for the anticancer activity of HDAC inhibitors, which include the enhanced acetylation of core histones and consequent increased accessibility of genomic DNA to transcriptional complexes, resulting in the induction of tumor suppressor genes.…”

“…Several small-molecule HDAC inhibitors have recently been shown to exhibit potent and specific anticancer activity in preclinical studies. (10)(11)(12)(13)(14) Multiple mechanisms have been proposed for the anticancer activity of HDAC inhibitors, which include the enhanced acetylation of core histones and consequent increased accessibility of genomic DNA to transcriptional complexes, resulting in the induction of tumor suppressor genes. (10,15) The hyper-acetylation of histones induced by the HDAC inhibitor trichostatin A (TSA) has been shown to increase chromatin accessibility by measurement of the size-dependent nuclear distribution of microinjected fluorescein isothiocyanate-dextran conjugates with the use of image-correlation spectroscopy.…”

Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells

“…We have also recently shown that the MEK inhibitor PD184352 enhances the induction of apoptosis by histone deacetylase inhibitors in a variety of tumor cells with constitutive activation of the ERK pathway [14].…”